Role of HNF4? in control of bile acid synthesis and conjugation. Among the many interesting phenotypes in the HNF4? liver null mice (HNF4?deltaL) is an elevation in serum bile acids. HNF4?deltaL mice have markedly increased levels of serum bile acids (BAs) compared with control floxed mice (HNF4?F/F). Because bile acids are produced from cholesterol in liver and many enzymes involved in their biosynthesis are preferentially expressed in liver, the role of HNF4? in BA production was examined. This is due in part to the downregulation of genes encoding oxysterol 7?-hydroxylase (CYP7A1), sterol 12?-hydroxylase (CYP8B1), and sterol carrier protein x. CYP7A1 mRNA and protein were diminished only during the dark cycle in HNF4?deltaL mice, whereas expression in the light cycle was not different between HNF4?deltaL and HNF4?F/F mice. CYP8B1 mRNA and enzyme activity was reduced regardless of light or dark cycle. An HNF4? binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4?-dependent transcription. Surprisingly, cholic acid-derived BAs, produced as a result of CYP8B1 activity, were still observed in the serum and gallbladder of these mice. These studies reveal that HNF4? plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain ?-oxidation of cholesterol in vivo.HNF4?deltaL mice also exhibited decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), also called bile acid-CoA ligase, and bile acid-CoA:amino acid N-acyltransferase (BAT). This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder of the HNF4?deltaL mice. In agreement with this in vivo finding, HNF4? was also found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4?-binding sites and HNF4? expression by direct regulation of VLACSR and BAT in vivo. These studies indicate HNF4? plays a central role in bile acid synthesis and conjugation and explain why the HNF4?deltaL mice have abnormal bile acid homeostasis.Other genes controlled by HNF4?. A number of other genes are controlled by HNF4? as revealed by their down-regulation in HNF4?deltaL mice. These include the genes encoding blood coagulation factors FXII and FXIIIB, UDP-glucuronosyltransferase 1A9, and proline oxidase, uridine phosphorylase. These genes were also shown to have functional HNF4? binding sties. In the pancreatic ?-cells, HNF4? was shown to influence the expression of the K(ATP) channel activity thus explaining in part its association with maturity onset diabetes of the young, type 1 (MODY1).